Riluzole Found Ineffective for Huntington's Disease Patients

Marsha L. Miller, Ph.D., Sun, 08/19/2007

A Phase III clinical trial of the glutamate blocker rizuole failed to slow progression or improve symptoms in HD patients.

The results of this Phase III clinical trial with random assignment to the treatment or placebo groups and double-blind assessment of results are clear. There is no reason for Huntington's Disease patients to take riluzole. It neither slows progression nor improves symptoms.

The theory behind trying riluzole is that it might address excitotoxicity which is thought to be a major pathology in Huntington's Disease. The idea is that the overstimulation of N-methyl-d-aspartate (NMDA)-type glutamate receptors causes a variety of problems, including excessive calcium in the associated ion channels, which eventually lead to cell death. Researchers know that this is a problem in stroke and brain injury, and have reason to believe that it also occurs in chronic neurological diseases albeit in a slower manner. There have been several unsuccessful HD trials of glutamate blockers. Remacemide and lamotrigine were also found to be ineffective.

The drug memantine, which stabilizes rather than blocks or inhibits this important neurotransmitter may have more promise. Some open label studies have suggested that it might slow progression and anecdotal reports have suggested it may lead to cognitive improvement. The Lighthouse is eagerly awaiting the results of a clinical trial designed to show whether memantine improves memory and concentration.

Our thanks go to the participants in the riluzole clinical trials. Although we did not get the positive results researchers had hoped for, it is important to keep trying. Researchers learn from negative results as well as positive ones.

We conducted a randomized double-blind trial of riluzole in Huntington's disease to investigate the efficacy of this antiexcitotoxic drug in slowing disease progression.

Methods:

The study included 537 adult patients with a clinical diagnosis of Huntington's disease confirmed by genotyping. Patients were randomized (2:1) to treatment with riluzole (50mg twice daily) or placebo for 3 years. Concomitant use of antichoreic medication was forbidden, and introduction of such medication was a predefined end point. The primary outcome measure was change in a combined score derived from the motor and total functional capacity subscores of the Unified Huntington's Disease Rating Scale. Safety was also evaluated.

Results:

A total of 379 patients completed the study (mean age, 47 [standard deviation, 9.5] years; 50% female patients). The principal reason for discontinuation was introduction of antichoreic medication. The median change from baseline in the combined score (primary outcome) for the "per protocol" population was 13.7 (95% confidence interval, 11.1-17.2) in the placebo group and 14.3 (95% confidence interval, 11.7-16.6) in the riluzole group. No intergroup difference in outcome could thus be demonstrated (p = 0.93, Mann-Whitney U test). No differences in secondary efficacy outcome variables were observed except for more frequent recourse to antichoreic medication in the placebo group. No unexpected adverse events were reported, and tolerability was acceptable.

Interpretation:

No neuroprotective or beneficial symptomatic effects of riluzole in Huntington's disease were demonstrated. Ann Neurol 2007.